aCentre for Respiratory Disease Research, and bCentre for Microbiology Research, Kenya Medical Research Institute, Nairobi, Kenya; cFred Hutchinson Cancer Research Institute, Seattle, WA, USA; dDepartment of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; and eCurrent affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, CA, USA.
Sponsorship: This work was supported by a grant from the Rockefeller Foundation.
Written informed consent was obtained from each participant in the study. The protocol was approved by the Ethical Review Committee at the Kenya Medical Research Institute, Nairobi, Kenya.
Received: 4 March 2003; revised: 17 April 2003; accepted: 28 April 2003.
We evaluated a modified WHO algorithm for the management of chronic diarrhoea in ambulatory HIV-1-infected adults that included the use of norfloxacin, metronidazole and loperamide. In a cohort of 380 HIV-1-infected adults in Nairobi, Kenya, the incidence of chronic diarrhoea was 286 cases/1000 person-years; 85% of chronic diarrhoea episodes responded completely to therapy. Although these findings appear to validate the modified WHO chronic diarrhoea algorithm, randomized controlled trials may better define the indication for antibiotics in chronic diarrhoea.
In sub-Saharan Africa, chronic diarrhoea often presents with significant weight loss [1,2], eventually occurs in 60–90% of HIV-infected adults , and causes significant mortality . Most studies of chronic diarrhoea performed in Africa have enrolled hospitalized rather than ambulatory patients [5,6]. Furthermore, the isolation of few treatable enteric pathogens in most cases of HIV-associated chronic diarrhoea has complicated the development and testing of locally applicable management strategies [7,8]. In this study, we managed cases of chronic diarrhoea presenting to an outpatient facility using a modified version (Fig. 1)  of the WHO chronic diarrhoea guideline  for HIV-1-infected adults.
A cohort of 380 HIV-1-infected adults was formed over a 6-month period, from July 1997, and was followed every 2 months to January 2000. At the initial visit, CD4 T-lymphocytes were enumerated (Becton Dickenson, Sunnyvale, CA, USA). A modified WHO algorithm was used to manage patients presenting with chronic diarrhoea defined as three or more loose stools intermittently or continuously for at least one month (Fig. 1). Those with a history of antibiotic use in the previous 2 weeks were excluded from participation. The WHO algorithm recommended trimethoprim–sulfamethoxazole (TMP–SSX), metronidazole and loperamide for the management of chronic diarrhoea. Norfloxacin was substituted for TMP–SSX as a result of observed resistance . Loperamide 2 mg was given as an initial dose, followed by repeated 2 mg doses after every episode of diarrhoea if symptoms worsened, remained unchanged, or were particularly severe at initial presentation. Clinical cure was defined as two or less formed stools per day. Stool specimens were obtained for microscopy, culture and sensitivity, including acid-fast staining for Mycobacterium tuberculosis following standard procedures .
SPSS for Windows 9.0 (SPSS Inc., Chicago, IL, USA) was used to evaluate potential risk factors for the first episode of chronic diarrhoea and to assess factors related to cure rate. Multivariate logistic regression was performed to calculate adjusted rate ratios (ARR), the final model being selected using backward elimination. As duration of participation varied, length of follow-up was always included as a covariate in the regression.
The initial characteristics of this cohort have previously been reported . At enrollment, 29 individuals (8%) had CD4 T-cell counts less than 50 cells/μl, 94 (25%) had counts of 50–199 cells/μl, 159 (42%) had counts of 200–499 cells/μl, and 89 (23%) had counts of 500 cells/μl or greater. According to the CDC classification system for HIV-1 infection, 61 individuals (16%) were asymptomatic, 196 (53%) were symptomatic without an AIDS-defining illness, and 117 (31%) had an AIDS-defining condition .
The median length of follow-up was 552 days (range 1–831 days). One hundred and forty-eight episodes of chronic diarrhoea were diagnosed in 85 individuals; 53 suffered from a single episode whereas 33 were diagnosed with more than one episode of chronic diarrhoea. The overall incidence of chronic diarrhoea was 286 per 1000 person-years. In multivariate analysis, while controlling for length of time in the cohort, age 30 years or greater [ARR 1.8, 95% confidence interval (CI) 1.1–2.6], male sex (ARR 1.5, 95% CI 1.0–2.2), initial CD4 T-cell count less than 200 cells/μl (ARR 1.6, 95% CI 1.1–2.2), a history of chronic diarrhea (ARR 2.6, 95% CI 1.5–3.7), and 10% or more weight loss (ARR 1.7, 95% CI 1.1–2.3) during the year before enrollment were associated with an increased risk of chronic diarrhoea.
Of the 85 individuals diagnosed with chronic diarrhoea, those with less than 8 years of education [17/33 (52%) in comparison to 8 or more years of education 15/50 (30%) P = 0.05], and not treated with metronidazole for their first episode of chronic diarrhoea [9/15 (60%) versus 23/70 (33%) P = 0.05] more likely suffered recurrent chronic diarrhoea.
Overall, 125 out of 148 (85%) episodes of chronic diarrhoea responded completely to treatment. Of the 85 individuals experiencing their first occurrence of chronic diarrhoea, a similar proportion, 72 (85%) also had complete resolution of symptoms as previously defined. Eleven chronic diarrhoea episodes (7%) required intravenous rehydration and hospitalization.
Only analysing the first episode of chronic diarrhoea, we constructed a multivariate model to evaluate factors that might be associated with the resolution of symptoms. Not using metronidazole (P < 0.03), the presence of bacteria (not including M. tuberculosis) on culture (P = 0.06), a history at enrollment of chronic diarrhoea (P < 0.03), and being widowed (P < 0.01) were associated with a decreased cure rate. The identification of ova and cysts (P = 0.63) and age (P = 0.10) were not associated with the resolution of chronic diarrhoea, but were retained in the final model as they tended to confound the effect of the other factors.
Stool samples were collected for culture in 96 out of 148 episodes of chronic diarrhoea (65%); for the remainder of the cases participants were unable to produce stool at the time of visit. Out of these 96 episodes of chronic diarrhoea, 34 (35%) had potential pathogens detected, of which 22 (62%) were considered to be potentially treatable. Mycobacterium spp. (13%) was the most common organism, followed by Cryptosporidium spp. (11%), Salmonella spp. (6%) and Shigella spp. (3%).
Although a few studies have measured the incidence and described risk factors for chronic diarrhoea in HIV-1-infected adults living in developing countries, this is the first attempt to validate a simple treatment algorithm for chronic diarrhoea. Although subjects received virtually all of their medical care at the study clinic, leading to the accurate detection of chronic diarrhoea, loss to follow-up probably caused an underestimation of the true incidence of chronic diarrhoea. The incidence of chronic diarrhoea was less than half that recently found in an HIV-1-infected Ugandan cohort . However, the Ugandan study reported a median CD4 cell count of 215 cells/μl at enrollment in comparison to 300 cells/μl in the current study, and included both acute and chronic cases .
Overall, the modified WHO clinical guideline performed well, with 85% of chronic diarrhoea episodes clinically responding to treatment. In Zambia, 43% of HIV-1-infected hospitalized patients with chronic diarrhoea demonstrated spontaneous remission , whereas in a separate study , 39 and 21%, respectively, showed complete and partial responses after 14 days of treatment with albendazole. The infrequent need to hospitalize and rehydrate patients in our study probably partly accounts for the higher cure rate than found in Zambia. In the future, randomized controlled trials may help explain the role of antibiotics or other newer agents such as nitazoxanide in the management of HIV-1-associated chronic diarrhoea .
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: 663–666.#m AcknowledgementsThe authors wish to thank Cleopa Omondi, Belinda Muchina, Lilian Makhandia, Jamine Ogonda, Henry Karuchi, S.K. Kamwati and Lucy Sanguli for providing excellent care and support for the study participants.